Interactions between histaminergic and cholinergic systems in
learning and memory
Lucia Bacciottini, Maria Beatrice Passani, Pier Francesco Mannaioni,
Patrizio Blandina *
Dipartimento di Farmacologia Preclinica e Clinica, Uni6ersita´ di Firenze, Viale G. Pieraccini6,50139Firenze, Italy
Received 22 September 1999; accepted 27 June 2000
Abstract
The aim of this review is to survey biochemical, electrophysiological and behavioral evidence of the interactions between the cholinergic and histaminergic systems and evaluate their possible involvement in cognitive processes. The cholinergic system has long been implicated in cognition, and there is a plethora of data showing that cholinergic deficits parallel cognitive impairments in animal models and those accompanying neurodegenerative diseases or normal aging in humans. Several other neurotransmit-ters, though, are clearly implicated in cognitive processes and interact with the cholinergic system. The neuromodulatory effect that histamine exerts on acetylcholine release is complex and multifarious. There is clear evidence indicating that histamine controls the release of central acetylcholine (ACh) locally in the cortex and amygdala, and activating cholinergic neurones in the nucleus basalis magnocellularis (NBM) and the medial septal area-diagonal band that project to the cortex and to the hippocampus, respectively. Extensive experimental evidence supports the involvement of histamine in learning and memory and the procognitive effects of H3 receptor antagonists. However, any attempt to strictly correlate cholinergic/histaminergic
interactions with behavioral outcomes without taking into account the contribution of other neurotransmitter systems is illegitimate. Our understanding of the role of histamine in learning and memory is still at its dawn, but progresses are being made to the point of suggesting potential treatment strategies that may produce beneficial effects on neurodegenerative disorders associated with impaired cholinergic function. © 2001 Elsevier Science B.V. All rights reserved.
Keywords:Acetylcholine; Histamine; Amygdala; Hippocampus; Cerebral cortex; Release
1. Introduction
The extensive loss of cholinergic neurons in the basal forebrain, detected at autopsy [104] and, more recently, using chemical imaging [73], is the most salient neuro-chemical feature of Alzheimer’s disease [27], and has been linked to cognitive impairment [105]. Further-more, both cholinergic [32] and memory deficits [72] occur also in normal aging, although these dysfunctions differ qualitatively and quantitatively from those re-ported in AD. These observations, together with a
wealth of data showing that anticholinergic drugs, such as scopolamine and atropine, produced learning and memory deficits [25,35,44], have led to the cholinergic hypothesis of geriatric cognitive dysfunction [10]. As a result, much of the research on cognitive decline has focused on the role of central acetylcholine (ACh) [41], and related treatment strategies have traditionally aimed at restoring the cholinergic neurotransmission. However, therapies with cholinesterase inhibitors or muscarinic agonists have been generally unproductive [69], being improvements of cognitive functions gener-ally modest and confined to a minority of patients, although whether such therapies provide protection against further cognitive decline is still being evaluated [103]. These drugs may disrupt the normal pattern of cholinergic transmission, thus blocking proper signal
* Corresponding author. Tel.: + 4271239; fax: + 39-055-4271280.
E-mail address:blandina@server1.pharm.unifi.it (P. Blandina).
0166-4328/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 6 - 4 3 2 8 ( 0 1 ) 0 0 2 3 0 - 3
processing. In addition, over the past decade much evidence has shown that the ‘cholinergic hypothesis of learning’ [10] is too reductionistic. [58,112]. Different
pathological manifestations of AD, such as
b-amy-loidosis, presence of tangles and dystrophic neurites, synapse loss and various neurotransmitters deficits ren-der unlikely that cholinergic dysfunction could account for all cognitive and non-cognitive symptoms. Further-more, several neurotransmitters, including dopamine, GABA, noradrenaline, serotonin and histamine, are clearly implicated in cognitive processes and interact with the cholinergic system [33,99]. Since abnormalities of these neurotransmitter systems have been identified in Alzheimer’s disease and aging [1,57], these alterations might well interact with those of ACh to cause additive or even synergistic effects on cognition. For instance, the role of serotonin in learning and memory has received much interest [76], although the data appear to be rather inconsistent [76]. Nevertheless, 5HT3
antago-nists seemed to improve the performance of rodents and primate in various cognitive tests [102], possibly through modulation of cholinergic mechanisms [52]. Also dopamine, especially the mesocortical system, is thought to have a crucial role in learning and memory [74]. Increased dopamine turnover in the
pre-fontal cortex impaired spatial memory
per-formance [88]. In the auditory cortex an increase of dopaminergic activity evaluated by microdialysis ap-peared to reflect the initial formation of the behav-iorally relevant association [120], and the phasic activation of mesocortical and mesolimbic dopaminer-gic systems is differentially influenced by associative and non associative learning mechanisms [11]. His-tamine implications in learning and memory is sup-ported by extensive experimental evidence [94,124], and there is evidence that histaminergic H3receptor
antago-nists facilitated memory acquisition [51], possibly through cholinergic mechanisms [99]. Interestingly the
effect of tacrine
(1,2,3,4-tetrahydroamino-9-acridi-namine), which alleviates Alzheimer’s disease symptoms in some patients, may be partly due to multiple phar-macological mechanisms. Although protection of en-dogenous ACh is its most accepted mechanism of action, through acetylcholinesterase inhibition, tacrine was more potent to inhibit histamine-N-methyltrans-ferase, the enzyme responsible for brain histamine metabolism, than acetylcholinesterase [86]. The en-hancement of histamine brain level might be related with the activity of tacrine in Alzheimer’s disease. Thus, the role of interactions between ACh and other neuro-transmitters affecting cognition is of considerable inter-est. This review focuses on interactions between the cholinergic and the histaminergic systems and examines the possible role of such interactions in learning and memory.
2. Modulation of hippocampal cholinergic tone by histamine
The cholinergic system might be one of the most important modulatory neurotransmitter systems in the brain. It is distributed in a variety of different nuclei, two groups of which are localized in the forebrain. The nucleus basalis magnocellularis (NBM) is the major source of cholinergic innervation to the neocortex, and the amygdala, whereas the medium septum-banda diag-onalis complex (MSA-DB) provides cholinergic input to the hippocampus [78,89,135]. Since degeneration of these two cholinergic pathways is the most consistent damage occurring in Alzheimer’s disease [27], a large number of studies have investigated the regulation of either NBM or MSA-DB cholinergic neurons. These neurons appear to be interconnected with several neu-rotransmitters, such as dopamine, noradrenaline, sero-tonin, GABA, opioids, galanin, substance P and angiotensin II [33]. There is also much evidence sug-gesting that histaminergic system modulates both NBM and MSA-DB cholinergic pathways [13,100]. Indeed, histaminergic cell bodies are exclusively localized in the
tuberomammillary nucleus of the hypothalamus
[97,131], from where they project efferent fibers,
pre-Fig. 1. Schematic diagram of the sites at which cholinergic/histamin-ergic interactions might occur. Three systems may be of special interest, the nucleus basalis magnocellularis (NBM)/cortical system, the NBM/amygdaloid system and the medium septum-banda diago-nalis (MSA-DB)/hippocampal system. Drugs acting at H1receptors may affect cortical cholinergic tone by interacting with cholinergic perikarya in the NBM, whether directly or indirectly is not known yet. H2 receptor agonists or antagonists may affect the cholinergic tone in the amygdala at cholinergic terminals level. They may also modulate the hippocampal cholinergic tone by interacting with cholinergic perikarya in the MSA-DB, whether directly or indirectly is not known yet which. H3 receptor ligands may interact with autoreceptors in the septum and the amygdala, thus modulating indirectly the cholinergic tone in the amygdala and the hippocampus. They may also thus affect cortical cholinergic activity by acting at postsynaptic H3receptors localized on GABAergic neurons.
dominantly ipsilaterally and with multifold arboriza-tions, into the whole central nervous system, including the NBM, MSA-DB, amygdala, hippocampus and cere-bral cortex [64,96,123,130]. Fig. 1 shows a schematic diagram of the sites at which cholinergic/histaminergic interactions might occur.
Hippocampus has long been thought to be an impor-tant cortical region for associative learning and mem-ory. An early study indicated that ACh release from the CA1 – CA3 region of hippocampus of anesthetized rats could be modulated by endogenous histamine [83]. Indeed, an electrical stimulation applied to the tubero-mammillary nucleus greatly increased both histamine
release from MSA-DB and ACh release from
hippocampus. Similar results were obtained when the hypothalamus was perfused with a 100 mM potassium-containing medium [83]. ACh release was increased through the release of histamine, since both ACh and histamine electrically-evoked releases were abolished in rats pretreated with a-fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase. This enzyme is essential for histamine synthesis [71], and its blockade caused a complete depletion of neuronal histamine [132]. ACh electrically-elicited release was inhibited by systemic administration of zolantidine, an H2 receptor
antagonist [21], but not of pyrilamine, an H1 receptor
antagonist, thus indicating that activation of H2
recep-tors resulted in an increase of extracellular level of
hippocampal ACh [83]. Stimulation of H2 receptors
released also endogenous noradrenaline from rat hypo-thalamic slices [16] and prolactin [34]. The implication of endogenous histamine was further supported by the observation that administration of thioperamide, an H3 receptor antagonist [4], increased, while that of R- a-methylhistamine, an H3 receptor agonist [4], decreased
ACh spontaneous release from hippocampus [83]. In-deed, the H3 receptor was initially discovered on
his-taminergic neurons as a presynaptic autoreceptor, whose activation inhibited the release of histamine, and its blockade elicited an increase of histamine extracellu-lar levels [4,5].
Electrical stimulation of tuberomammillary nucleus enhanced histamine release not only from MSA-DB, but also from hippocampus, thus indicating that it might act at both the cell bodies and the terminals of the cholinergic system [83]. However, since the electrical stimulation elicited a response in histamine release from MSA-DB six-fold greater than that elicited from hippocampus, it is perhaps more likely that an interac-tion between histaminergic and cholinergic systems oc-curred in the MSA-DB complex. These observations have been largely confirmed and extended, and it is clear yet that histamine exerts a tonic influence on hippocampal cholinergic activity only at MSA-DB-complex level. In fact, microdialysis experiments have failed to show an effect of histamine, applied locally to
hippocampus, on extracellular level of hippocampal ACh [8]. In the extension of this study, histamine receptor-selective compounds were applied by retro-grade microdialysis to the MSA-DB area of the rat brain, and the effects of this infusion on extracellular ACh in hippocampus were recorded with a second microdialysis probe [7]. Intraseptal administration of thioperamide increased significantly the spontaneous release of ACh from hippocampus of freely moving rats
by up to about 100% [7]. Cimetidine, an H2 receptor
antagonist [38], fully antagonized the effect of thiop-eramide. Also cimetidine was administered locally into the septum [7]. Thus, assuming that intraseptal admin-istration of thioperamide produced an increase of en-dogenous histamine extracellular levels, this study further supports the suggestion that histaminergic neu-rons projecting to the septum [96] facilitate hippocam-pal cholinergic activity. The blockade of thioperamide effect on hippocampal ACh release by cimetidine sug-gests that endogenous histamine interacted with postsy-naptic H2receptors, although it is not yet clear whether
H2 receptors are located on the septal cholinergic cell
bodies, or on hypothetical neurons, which in turn facil-itate the release of hippocampal ACh. Also intraseptal
administration of ciproxifan, another H3 receptor
an-tagonist [75], increased ACh spontaneous release from hippocampus of freely moving rats by about 100%, and its effect was fully antagonized by cimetidine [6], thus confirming the hypothesis that histaminergic efferents to the septum facilitate hippocampal cholinergic activ-ity through H2 receptor activation.
Electrophysiological findings indicated that histamine depolarized MSA-DB cholinergic neurons in a slice preparation of rat brain, producing an increase in sodium conductance which led these neurons to threshold for firing spontaneous action potentials [54].
The effect was attributed to H1 receptor activation,
since it was significantly reduced by mepyramine (also
known as pyrilamine) and promethazine [54], both H1
receptor antagonists [61]. However, the concentrations employed were very high, and the authors may have underestimated additional nonspecific properties of these two compounds [60]. Moreover, depolarization induced by histamine was transient, being desensitiza-tion within seconds, its prominent feature and the excitation diminished despite continued application of histamine [54]. If the effect on ACh release was very rapid, it is possible that it became obscured during the attainment of the 20-min perfusion sample, thus ex-plaining why the biochemical studies mentioned above have failed to find an effect of H1receptor blockade on
septohippocampal cholinergic activity. In contrast to earlier cited microdialysis studies, Dringenberg and col-leagues [36] demonstrated that systemic administration of mepyramine caused a very large increase of ACh spontaneous release from hippocampus of
urethane-anesthetized rats, thus suggesting an implication also
for H1 receptors. The discrepancy between this study
and Mochizuki’s work [83], which failed to show any effect of mepyramine, may be related to differences in the doses used, 10 – 20 and 5 mg/kg, respectively.
More-over, these H1 receptor antagonists possess marked
antimuscarinic properties [59,60], and consequently their selectivity between the three different histamine receptors [61] does not guarantee an unambiguous characterization.
3. Modulation of c-fos expression by histamine
In addition to the effect on hippocampal ACh re-lease, c-fos immunoreactivity was detected in the me-dial septum 90 min after intraseptal administration of ciproxifan [6]. Significantly fewer c-fos immunoreactive nuclei were seen in control. Also the effect of ciproxifan on c-fos expression was fully antagonized by cimetidine [6]. Morphological features indicate that c-fos was ex-pressed in neuronal cells, but the type of neuron has not been identified yet. The protoncogene c-fos is an immediate-early gene linked to genomic events in the cellular response to environmental signals [116], and has provided a useful marker for tracing the effects of pharmacological, electrical and physiological stimuli in the CNS [85]. Although increased hippocampal ACh release and c-fos expression might be dissociated pro-cesses, despite the identity of the stimulus, these obser-vations may have implications for the treatment of disorders associated with impaired septo-hippocampal cholinergic functions.
4. Modulation of cholinergic tone in the cortex and in the amygdala by histamine
In addition to the findings indicating interactions between histamine and the septo-hippocampal choliner-gic pathway, there is also evidence that histamine may have a regulatory role on the release of ACh also in the NBM-cortical and the NBM-amygdaloid pathways. Two different laboratories reported that histamine in-hibited potassium-evoked release of [3H]-ACh from rat
cortical slices preloaded with [3H]-choline through
acti-vation of H3 receptors [3,23]. The effects of histamine and agents acting at histamine receptors on sponta-neous and potassium-evoked release of ACh were also investigated in vivo, using microdialysis to simulta-neously administer histamine and monitor changes in endogenous ACh release from cortex of freely moving rats [14,15]. Histamine, administered locally into the cortex, failed to affect ACh spontaneous release. Con-versely, it inhibited concentration-dependently potas-sium-elicited release of ACh. The H3 receptor agonists
R-a-methylhistamine, imetit [46,62,126], and immepip [128] mimicked the effect of histamine, showing a slightly greater potency than histamine [14]. Oppositely, neither 2-thiazolylethylamine [45], an agonist showing some selectivity for H1 receptors, nor the H2 receptor agonist dimaprit [98] modified potassium-evoked
re-lease of ACh [14]. The inhibitory effect of 100 mM
histamine, a concentration producing the maximal
ef-fect [14], was completely prevented by histamine H3
receptor antagonists, such as clobenpropit [126] and thioperamide, but was resistant to antagonism by triprolidine [65] and cimetidine, antagonists at
his-tamine H1 and H2 but not H3 receptors [14,15]. All
agonists and antagonists were administered locally, dis-solved into the perfusion medium. The concentration of potassium used in these studies, 100 mM, is only appar-ently high, for the low recovery of potassium through the microdialysis membrane [134], and the rapid dilu-tion of potassium in the extracellular space necessitate high concentrations in the perfusion fluid. In fact, 60 mM potassium had only a slight effect on ACh release during brain dialysis [133], and perfusion of the cortex in vivo with 100 mM potassium evoked an increase in ACh release [14,15] similar to that obtained with
incu-bation of cortical slices in 20 mM potassium [23]. H3
receptor-induced inhibition of potassium-evoked release of ACh was completely abolished in cortices in which the traffic of action potentials was blocked by tetrodo-toxin, a voltage-dependent sodium-channel blocker [14].
Thus, H3 receptors modulating ACh release are likely
located neither presynaptically on cholinergic nerve ter-minals, nor on non-cholinergic nerve endings impinging on the former. They are most likely somatodendritic receptors on interneurons, the excitation of which pro-duced sodium-dependent action potentials that release an intermediary modulatory substance. Consistently, in synaptosomes of entorhinal cortex, the release of [3
H]-ACh remained unaltered in the presence of two H3
receptor agonists [3], thus strongly suggesting that H3
receptors modulating cortical ACh release are located postsynaptically on intrinsic perikarya [3]. Indeed, H3
receptors are not restricted to extrinsic histaminergic
nerve endings [107], and H3 receptor-mediated
inhibi-tion of the release of neurotransmitters other than histamine has been described [113]. Moreover, lesion
experiments demonstrated that H3heteroreceptor
num-ber present on intrinsic neurons or other target cells is, at least in some regions, much greater than that of H3
autoreceptors [107]. Consistently, degeneration of
perikarya by local infusion of kainate strongly de-creased the number of H3receptors in the striatum and
the cerebral cortex [26,107].
Recent microdialysis experiments demonstrated that bicuculline, a GABAAreceptor antagonist, reversed the
inhibition of ACh release induced by immepip, an H3
involve-ment [48]. Furthermore, immepip, at a concentration that produced a maximal inhibition of evoked ACh release [14] increased 100 mM potassium-evoked release of GABA from the cortex of freely moving rats by more than 50% [48]. Thus it is
conceiv-able that H3 receptors, localized postsynaptically on
intrinsic perikarya, facilitated GABA release, which, in turn, inhibited ACh release. The most simple
hypothe-sis is that GABA activated GABAAreceptors localized
on cholinergic nerve endings, thus reducing ACh re-lease. Experimental evidence suggests that the cortical GABAergic system exerts a tonic inhibition of sponta-neous release of ACh from the cortex, and that this inhibitory tone is maximal [49]. This could elucidate
why neither histamine nor either of H3 receptor
ago-nists altered spontaneous ACh release [14], much of which is tetrodotoxin sensitive [14]. Under resting con-ditions, since the inhibition of ACh release caused by
GABA is maximal, H3activation would have no effect
on spontaneous ACh release. However, activation of
H3 receptors, by increasing the release of GABA, will
antagonize the potassium-induced depolarization, thus, depress, at least partially, potassium-evoked acetyl-choline release. Alternatively, another synaptic
arrange-ment consonant with the lack of H3 modulation of
spontaneous release is that the activated interneurons inhibit the release of an excitatory presynaptic modula-tor of cholinergic terminals. If this excitamodula-tory pathway
were not spontaneously active, H3 activation would
have no effect on spontaneous ACh release. In the presence of potassium, this excitatory modulator would be released and enhance the depolarization-induced
release of ACh. Activation of H3 receptors would
re-move this enhancement and partially, but not com-pletely, depress potassium-evoked ACh release. Cortical GABA interneurons control the activity of large popu-lations of principal cells through their extensive axon arborization [42]. Therefore, any pathway, even if rela-tively sparse such as the histaminergic pathway, may exert a powerful effect on the activity of the cortex if it modulates the activity of local GABA interneurons.
Histaminergic modulation of cortical cholinergic tone appears to be complex and multifaceted, and consists of two components, one inhibitory related to local actions at the terminals, the other excitatory resulting from interactions with cholinergic cell bodies in the NBM. Indeed, an electrophysiological study in guinea-pig basal forebrain slices, reporting that histamine
depolar-ized NBM cholinergic mainly through H1receptor
acti-vation [70], suggests that histaminergic neurons might also facilitate cortical cholinergic release. An intact, whole animal approach yielded important insight into the physiological role of histamine in modulating corti-cal cholinergic activity, rats were implanted with two microdyalisis probes; one in the NBM to deliver locally the different drugs; and the other in the cortex to
measure the output of ACh [22]. The administration of histamine into the NBM increased concentration-de-pendent the output of ACh from the cortex of freely moving rats by about 100% [22]. ACh release elicited by
100 mM histamine was insensitive to blockade of H2
and H3 receptors by means of cimetidine and
thiop-eramide [22]. Conversely, triprolidine, an H1 receptor
antagonist, reduced significantly the effect of 100 mM
histamine [22]. Although, mechanisms concomitant to
H1 receptor activation cannot be excluded, both
elec-trophysiological and biochemical findings indicate that histamine in the NBM facilitates the cortical cholinergic activity, and strongly suggest that H1 receptor
activa-tion is, at least in part, responsible for this effect. The dual effect of histamine on cortical cholinergic activity, excitatory at the level of NBM cell bodies, and in-hibitory at the level of cholinergic terminals [14,48], may have implications for the treatment of disorders associated with impaired cortical cholinergic functions. The amygdala is involved in the cognitive evaluation of the emotional content of complex cues, and acquisi-tion of characteristic responses to aversive events de-pends on its integrity [122]. The basolateral nuclei, which receive major inputs from cortical and subcorti-cal sensory areas [29], also receive cholinergic innerva-tion from NBM [78] and histaminergic innervainnerva-tion from the hypothalamus [96]. Furthermore, autoradio-graphic and immunohistochemical studies have shown high densities of both H3[107] and muscarinic receptors
in this brain region [127]. Modulation of cholinergic transmission in the amygdala may be important for the acquisition or expression of relevant behaviors. Local administration of thioperamide decreased significantly the spontaneous release of ACh from basolateral nuclei of freely moving rats by about 50% [101]. This effect was fully blocked by cimetidine [101]. The inhibitory effect of thioperamide on ACh release may be ex-plained by an interaction with H3autoreceptors.
Block-ade of these receptors caused an increase of
extracellular levels of endogenous histamine [5]. There-fore, this study suggests that activation of histaminergic neurons projecting to the amygdala basolateral nuclei inhibits the cholinergic tone in this area. Postsynaptic H2receptors seem to mediate this effect, since
pretreat-ment with cimetidine fully antagonized the effect of
thioperamide. Whether H2 receptors are located on
cholinergic terminals, or on hypothetical interneurons is not clear yet.
5. Histamine and cognition
Despite the complexity of the neuromodulatory rela-tionship between cholinergic and histaminergic systems, a clear connection between histamine and learning and memory-related processes is provided by its
involve-ment in the induction of long term potentiation (LTP) in area CA1 of rat hippocampal slices [19]. LTP has been suggested to be the physiological correlate of memory formation [17]. Histamine-induced modulation of synaptic plasticity is not consequent to activation of classical histamine H1, H2or H3receptors [19], but it is attributable to an interaction with the polyamine-bind-ing sites on the NMDA receptor complex [12,129]. However, behavioral studies on animal models have provided extensive experimental evidence that the clas-sical histamine receptors are also involved in histamine effects on learning and memory. For example, immedi-ate post-training administration of histamine facilitimmedi-ated retention of a step-down inhibitory avoidance behavior, and this effect was antagonized by the simultaneous
administration of both prometazine, an H1 receptor
antagonist, and cimetidine, an H2 receptor antagonist
[30,31]. Consistently, histamine improved the response latency in a one-way active avoidance response of aged
rats [124]. This effect was mimicked by H1 receptor
agonists, and antagonized by H1 receptor antagonists
[124]. Aged animals are impaired in the acquisition of several learning procedures, such as both active and passive avoidance or maze learning [124]. Central his-tamine receptors are implicated also by findings that oral administration of classical H1receptor antagonists,
such as mepyramine and promethazine retarded the acquisition and impaired the retention of acquired learning in an active avoidance task, while H1 receptor
antagonists less liable to cross the blood brain barrier, such as astemizole and oxatomide, caused only a weak depression of the avoidance response [66]. Interestingly, histamine as well as acetylcholine antagonized the ef-fects of mepyramine [68], thus indicating that histamin-ergic and cholinhistamin-ergic central systems might exert a functional interaction in this behavior. In fact, although
mepyramine’s antimuscarinic properties are well
known, it seems unlikely that they accounted for this effect, since the dose of acetylcholine required for pre-venting mepyramine-elicited amnesia was clearly very high, ten times higher than that able to antagonize the inhibitory effect of atropine [68]. In these studies his-tamine was always administered intracerebroventricu-larly, since this amine doesn’t cross the blood – brain barrier [55]. It is, however, dubious whether or not injection of histamine truly reflects the actions of en-dogenous histamine in the brain. A possible answer to this question arises from investigations on the effects of
L-histidine. In fact, histamine in brain is formed from L-histidine, which is taken up by an active process, and
decarboxylated by a specific L-histidine decarboxylase
(EC 4.1.1.22), which is not saturated under normal conditions [56]. Therefore, administration ofL-histidine
raised brain histamine levels [115]. Administration of
L-histidine to hippocampus-lesioned rats amply
in-creased hippocampal histamine content, and reduced
significantly the lesion-induced deficits of both acquisi-tion and retenacquisi-tion of an active avoidance response [124]. L-Histidine also ameliorated learning deficits
in-duced by scopolamine in mice exposed to an elevated plus-maze test [79], and was effective in improving rat learning performances in the olfactory social memory test [108], which is based on the investigation time of a juvenile rat by an adult rat, and measures a form of short-term memory [125]. These improvements of learn-ing behaviors were mediated by newly synthesized brain histamine, since they were prevented by pretreatment with a-fluoromethylhistidine [79,124], although periph-erally administered histamine was ineffective [79].
Mepyramine antagonized L-histidine ameliorating
ef-fects, thus confirming a role of central H1 receptors
[79]. The blockade of L-histidine decarboxylase by
a-fluoromethylhistidine lowered histamine content in those cells, such as histaminergic neurons, where the amine turned over rapidly [132]. Administration of a-fluoromethylhistidine produced a significant suppres-sion of memory retrieval and learning acquisition of active avoidance response [67,124]. Interestingly, the duration of the response latency was highly correlated with the depletion of histamine content in specific brain areas, such as hippocampus and hypothalamus [67,124].
It is important to remark that effective doses of
a-fluoromethylhistidine failed to influence locomotor ac-tivity [67,93], thus supporting the hypothesis that the decrease of neuronal histamine was directly responsible for cognitive impairments. In contrast to the hypothesis that histamine improves cognitive function, other stud-ies implicate a negative role of histamine on learning
and memory processes. Rats treated with
a-fluoromethylhistidine showed increased learning abili-ties in a maze paradigm, where they had to learn to avoid a foot shock [20]. Moreover, localized histamine injections into rat hippocampus prolonged significantly the latency time to escape in an active avoidance re-sponse [2]. Recently, the effects of lesions of the tubero-mammillary nucleus on the performance of adult and aged rats in a set of cognitive tasks have been reported; in addition to a marked decrease in the number of histaminergic neurons, these lesions produced an im-provement in every cognition test applied, and strongly diminished the age-related learning deficits [43]. Since amplification of the reward after hypothalamic stimula-tion was demonstrated following bilateral lesions of the tuberomammillary nucleus [63], one might suggest that tuberomammillary nucleus lesions facilitated cognition by enhancing the function of the reinforcement system. Interestingly, the implication of these studies, that the histaminergic system might exert an inhibitory tone on cognitive processes, could be readily integrated with findings that brain histaminergic activity was higher in the elderly [109,110], and histamine content of rat brain increased with age [92]. In conclusion, a role of
his-Table 1
Effects of H3receptor antagonists on cognitive tasks Effect
Drug Behavior test Reference
Improvement Ciproxifan Five-choice [75] Passive Clobenpropit Improvement [51] avoidance Object Improvement [51] recognition Elevated FUB 181 Improvement [91] plus-maze
Thioperamide Social memory Improvement [108] test
Passive Improvement [51,77] avoidance
Object Improvement [51] recognition
thioperamide or clobenpropit to scopolamine-impaired mice (1 mg/kg, i.p.) only attenuated scopolamine-in-duced impairments in the elevated plus-maze test and the step-through passive avoidance test, [80 – 82]. The use of a higher dose of scopolamine might explain this discrepancy.
Object recognition and passive avoidance responses might involve cholinergic neurons of the NBM, since both tasks were impaired by the cholinergic antagonist
scopolamine [40,118]. In addition, axon-sparing
ibotenic acid bilateral lesions of NBM neurons, includ-ing the cholinergic ones, which provide the innervation to the cortex and to the amygdala [39,78], disrupted the performance of rats in both tasks [9,37,95,106]. In fact, these paradigms serve to measure a form of episodic memory, possibly localized in the frontal cortex [53] and the amygdala [95]. Cognitive improvements
pro-duced by administration of H3 receptor antagonists
might be the result of relieving the inhibitory action on cortical acetylcholine by local H3 receptors (see Section 4). A second potential mechanism that may have con-tributed to the effects of H3antagonists is the
modula-tion of endogenous histamine release. Endogenous histamine exerted a tonic influence on cholinergic neu-rotransmission, enhancing cholinergic activity at the level of cholinergic cell bodies in the basal forebrain [7,22,83]. Thus, H3 receptor antagonists, by increasing
the release of endogenous histamine, may facilitate cholinergic activity in brain areas crucial for cognitive functions. However, a beneficial effect on a scopo-lamine-induced deficit is a concomitant observation, but does not prove in anyway that cholinergic neurons are involved. Reversal of impairments observed in the above mentioned studies may be also due to histamine direct effects on cognition, and/or to histaminergic modulation of any number of transmitter systems. More persuasive evidence of a close relationship be-tween the cholinergic and histaminergic system in learn-ing and memory is offered by the results of experiments
with H3 receptor agonists. Rat systemic pre-training
administration of imetit and R-a-methylhistamine mod-erated potassium-evoked release of cortical ACh and impaired performance in object recognition and a pas-sive avoidance response [14]. The disruption of the cortical cholinergic system may account for the cogni-tive impairments, since reduced availability of ACh in the synaptic cleft appeared related to cognitive deficits [111]. The lack of effectiveness of the same doses of
imetit and R-a-methylhistamine when administered
post-training, suggests that the H3 receptor is involved
in the acquisition but not the recall of this information [51]. However, ACh may control both acquisition and retention processes, since also post-training administra-tion of scopolamine resulted in animals exhibiting sig-nificantly shorter escape latencies during a passive avoidance response, and spending similar amount of tamine in learning and memory processes is highly
probable, but at present experimental evidence appears to be inadequate to enable firm conclusions to be drawn on this role. The knowledge of the distinct and possibly opposing modulatory actions that histaminer-gic tuberomammillary neurons might exert by activat-ing different receptor subtypes on specific neuronal networks involved in different learning processes may help resolve the controversy concerning its role in cognition.
Promising data have been obtained with H3 receptor
antagonists, which have been found to improve the performance of rodents in various cognitive tests (Table
1). Indeed, thioperamide, an H3 receptor antagonist,
improved rat performance in the olfactory, social mem-ory test [108]. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration [75]. Ciproxifan is a potent and
selective H3 receptor antagonist, which, being orally
bioavailable, appears promising for therapeutic applica-tions in aging disorders. Other studies, however,
re-ported that the procognitive effects of H3 receptor
antagonists became fully evident only when behavioral deficits were pronounced. For example, while thiop-eramide improved significantly, the response latency in a passive avoidance response in senescence-accelerated mice (these animals showed a marked age-accelerated deterioration in learning tasks of passive avoidance), it was ineffective in normal-rate aging mice [77].
Consis-tently, two H3 receptor antagonists, thioperamide and
clobenpropit [126], lacked any procognitive effect in control animals [51], but fully reverted rats cognitive impairments, measured in a passive avoidance response and object recognition, caused by injection of scopo-lamine (0.2 mg/kg, i.p.) [51]. Similarly, FUB 181,
an-other H3 receptor antagonist [119], significantly
ameliorated performances of scopolamine-impaired mice (0.5 mg/kg, i.p.) in the elevated plus-maze test [91]. Other studies, however, reported that administration of
time exploring new and familiar objects [51]. Therefore, the impairment of cognition by H3 receptor agonists is
unlikely attributable solely to the modulation of corti-cal acetylcholine. One might envisage mechanisms other
than the cholinergic one, and the finding that R-
a-methylhistamine improved rodent spatial learning and memory, assessed using a water maze [117], supports this contention. Spatial learning is a primary function of the rodent hippocampus [90], and the water maze test is exquisitely sensitive to hippocampal lesions [87],
but H3 receptor stimulation is expected to decrease
hippocampal cholinergic activity [6,7].
6. Conclusions
For the complexity of the neuronal networks in the brain, it seems naı¨ve to assume that only one neuro-transmitter, namely ACh, regulates such a complex mechanism as learning and memory. Other neurotrans-mitter systems have been implicated in these processes. Decker and McGaugh [33] suggested a model in which, although ACh has a central role, interactions with other neurotransmitters, such as dopamine, GABA, noradrenaline, are essential for the formation of mem-ory. This hypothesis is supported by several studies [18,52,112,121]. However, the modulation of the cholin-ergic pathways by other neurotransmitter systems, and the importance of the cholinergic system as a final effector in learning and memory, still needs to be defined. The aim of this review is to critically assess biochemical, electrophysiological and behavioral evi-dence of interactions between the cholinergic and the histaminergic systems, and to examine the possible role of such interactions in learning and memory. Biochemi-cal as well as electrophysiologiBiochemi-cal evidence indicates that ACh/histamine interactions appear to be complex and multifaceted (Fig. 1). Histamine activates cortical
H3 receptors, which are likely localized on GABA
interneurons, and inhibits the release of cortical ACh through a GABAergic mechanism [14,48,50]. On the other hand, histaminergic projections to NBM exert a tonic influence on cortical cholinergic activity, depolar-izing cholinergic cell bodies through activation of H1
receptors [22,70], thus increasing ACh release from the cortex [22]. Conversely, activation of histaminergic neu-rons projecting to the basolateral nuclei of the amyg-dala inhibits the cholinergic tone in this area, and
postsynaptic H2 receptors seem responsible for this
effect [101]. Finally, histamine effects on hippocampal cholinergic activity may involve actions at different anatomical locations. Local administration of histamine failed to affect ACh release from hippocampus, but MSA-DB endogenous histamine facilitates hippocam-pal cholinergic activity through activation of
postsy-naptic H2 receptors possibly localized on septal
cholinergic perikarya [6,7,83]. It is obvious that any attempt to strictly correlate physiological data with the outcome of behavioral tests is destined to fail. In sev-eral circumstances, though, one may envisage possible scenarios to account for the memory improving or impairing effects of histaminergic compounds in terms of modifications of ACh release. As an example, the depressant effect of H1antagonists on active avoidance
response seems consistent with the action of H1
recep-tors on NBM cholinergic neurons. A potential mecha-nism that may contribute to procognitive effects of H3
antagonists is the modulation of endogenous histamine release, which is under an inhibitory feedback control
by H3 autoreceptors [5,84]. Endogenous histamine
ex-erts a tonic influence on cholinergic neurotransmission, enhancing cholinergic activity at the level of cholinergic cell bodies in the NBM and MSA-DB [7,22,83]. Thus
H3 receptor antagonists, by increasing the release of
endogenous histamine, may facilitate cholinergic activ-ity in brain areas crucial for cognitive functions. It should be kept in mind, though, that the systemic administration of these histaminergic compounds can not account for a selective action on restricted brain regions. The scenario is certainly more complex; indeed, R-a-methylhistamine-induced improvement of rat per-formance in a water maze test [117] calls for a different explanation than simple ACh/histamine interactions. R-a-methylhistamine modulates, in addition to ACh, the release of either 5-HT or noradrenaline [114], and each of these transmitters has been shown to alter performance in a variety of cognitive tests [33]. There-fore, the possibility that at least some cognitive effects of histamine and histaminergic agents occur indepen-dently of ACh, cannot be excluded. It is also important to note that cognitive tasks don’t necessarily imply that all behavioral changes should be interpreted in terms of learning and memory, since the link between the behav-ioral change and a cognitive process is not a one-to-one relationship. For instance, in a water maze test, escape latency may reflect not only the ability to learn the position of the hidden platform, but also exploratory aspects of the behavior.
While our understanding of the histaminergic system and its role in learning and memory is far from com-plete, we have progressed to the point where it is possible to address the importance of treatment strate-gies that, taking advantage of non-cholinergic drugs that potentiate cholinergic functions, may produce beneficial effects on disorders associated with impaired cholinergic functions, such as Alzheimer’s disease [24]. This indirect approach appears preferable over choli-nomimetic strategies. In fact, cholinergic drugs used in most clinical trials have resulted in greater stimulation of inhibitory autoreceptors either by increasing the half-life of acetylcholine in the synaptic cleft [28] or by directly activating these receptors due to the poor
selec-tivity of the agonists available [47]. Indirect stimulation of residual cholinergic neurons may be achieved with appropriate pharmacological intervention. Thus, H3 re-ceptor antagonists could correct the deficits resulting from cholinergic hypofunction, and provide a novel approach to improve cognitive deficits.
Acknowledgements
This work was supported by grants 40%
(M.U.R.S.T) and 60% (M.U.R.S.T.-Universita´ di
Firenze, Italy).
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